EP0302894B1 - Procede de culture de leucocytes - Google Patents

Procede de culture de leucocytes Download PDF

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Publication number
EP0302894B1
EP0302894B1 EP87903509A EP87903509A EP0302894B1 EP 0302894 B1 EP0302894 B1 EP 0302894B1 EP 87903509 A EP87903509 A EP 87903509A EP 87903509 A EP87903509 A EP 87903509A EP 0302894 B1 EP0302894 B1 EP 0302894B1
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EP
European Patent Office
Prior art keywords
cells
leukocytes
culturing
hollow fiber
cultured
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP87903509A
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German (de)
English (en)
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EP0302894A4 (fr
EP0302894A1 (fr
Inventor
Georgiann B. Melink
Raji A. Shankar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Endotronics Inc
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Endotronics Inc
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Publication date
Application filed by Endotronics Inc filed Critical Endotronics Inc
Priority to AT87903509T priority Critical patent/ATE82588T1/de
Publication of EP0302894A4 publication Critical patent/EP0302894A4/fr
Publication of EP0302894A1 publication Critical patent/EP0302894A1/fr
Application granted granted Critical
Publication of EP0302894B1 publication Critical patent/EP0302894B1/fr
Expired legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
    • C12M25/10—Hollow fibers or tubes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
    • C12M29/16—Hollow fibers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C12N2501/23—Interleukins [IL]

Definitions

  • the present invention relates to in-vitro culturing of purified human leukocytes, and in particular, the present invention relates to a method of culturing of purified human leukocytes in a perfusion culturing system.
  • Adoptive immunotherapy in the contents of the present application involves the administration of immunologically active (immunocompetent) cells to an individual. These immunocompetent cells are taken either from the individual to be treated or from another individual. The purpose of administering immunocompetent cells to an individual is to provide a beneficial effect to the patient. For example, in the case of a cancer, cells are provided for the purpose of regressing and/or destroying a cancerous tumor.
  • Adoptive immunotherapy has been attempted by transferring immunocompetent cells from healthy animals to animals with a cancerous tumor.
  • animal experiments have suggested that an anti-tumor effect can be obtained with a high degree of antigen-specificity in certain tumor models. It has been found that the anti-tumor effect has been limited to certain tumors; and given the antigens-specificity of the effect, it has been assumed that in those cases (where antibodies have been ruled out as the effect or an important media of the effect) that leukocytes which include lymphocytes were involved.
  • NK natural killer
  • LAK lymphokine-activated killer
  • CTL cytotoxic T lymphocytes
  • NK and LAK cells are part of the immune system which preferentially lyse and/or kill target cells, including virally-infected and tumor cells.
  • Rosenberg et al., J, Biol. Response Modif. 3: 501-511 (1984) have shown in animal models, as well as in man, that lymphocytes obtained from peripheral blood in man or spleen in mouse can be activated within and for a very few days with recombinant interleukin-2 (rIL-2), a factor that activated certain lymphocytes such as LAK cells.
  • rIL-2 recombinant interleukin-2
  • Rosenberg et al. have shown that LAK cells will have a regressive effect on tumors both in-vitro and in-vivo. This methodology has been applied to the treatment of cancer in man and encouraging results have been obtained in a significant number of patients, especially those with hypernephroma, melanoma and tumors of the colon.
  • US-A 391 912 discloses the culturing of different kinds of cells, e.g. tumor cells, leukemic cells and lymphocytes, in a hollow fiber cartridge.
  • Mule et al., Science (1984) 225,p. 1487-1489, describe the culturing of lymphocytes in the presence of IL-2 in static cultures to produce lymphokine activated cells and their use in immunotherapy.
  • the present invention is directed to a method of culturing leukocytes wherein the leukocytes are cultured in a perfusion system in the presence of a lymphokine.
  • the leukocytes are cultured in an extracapillary space of a hollow fiber cartridge using a perfusion culturing system.
  • the leukocytes are cultured for at least four days and up to 19 (optimal 12-16 days) providing a harvestable yield of a least 100% to 5900% recovery and having lytic activity at least equal to that of leukocytes cultured in a static culturing system.
  • the cells are cultured with rIL-2 alone or rIL-2 and anti-CD3 monoclonal antibody. (Recent data suggests Anti-CD3 monoclonal antibody plus rIL-2 has been found to expand the cell number 10 fold greater than rIL-2 alone. A. Ochoa, et al.)
  • Figure 1 is a diagrammatical view of a cell culturing system used in the method of the present invention.
  • the present invention includes a method of culturing leukocytes in a perfusion system such that a harvestable yield of at least 100% to 5900% recovery of leukocytes having lytic activity is achieved.
  • leukocytes white blood corpuscles (cells) that combat infection.
  • lymphocytes are meant those leukocytes without cytoplasmic granules.
  • Lymphocytes normally number from 20% - 50% of total leukocytes and average 10-12 micrometers in diameter, but may be as large as 20 micrometers. Lymphocytes are characterized by a deeply-staining, compact nucleus taking a dark blue. The nucleus occupies all or most of the cell, either in the center or at one side. The cytoplasm is usually clear, but in some cells bright red-disk-violet granules are seen.
  • monocytes is meant a large mononuclear leukocyte having more protoplasm than a lymphocyte.
  • lymphokines are meant those factors which, when presented to lymphocytes, activate the lymphocytes to lytic activity wherein the lymphokine-activated cells lyse and/or kill tumor cells.
  • lymphokines are recombinant interleukin-2 (rIL-2), Beta-interleukin-1, Beta-interferon, alpha interferon and anti-CD3 monoclonal antibody.
  • lytic activity is meant the ability of a cell to destroy a target cell or tumor.
  • the present invention includes the culturing and maintenance of leukocytes in a hollow fiber cartridge perfusion culturing system such as is described in U.S. Patent No. 4,804,628 entitled “Improved Hollow Fiber Cell Culture Device and Method of Operation,” assigned to the same assignee as the present application, and which is hereby incorporated by reference.
  • the ACUSYST-P cell culturing system is diagrammatically illustrated in Figure 1.
  • the ACUSYST-JR is a scale down model of an ACUSYST-P, composed of one hollow fiber cartridge rather than 2-6.
  • the system generally indicated at 10 includes a primary media circulation system 12 and a secondary media circulation system 14 for circulating medium within a hollow fiber cartridge 16.
  • the circulation system 12 includes a primary medium supply 18 and a pump 20, preferably a bellows-type pump, connected by tubing 22.
  • the pump 20 is fluidly connected by tubing 24 to the hollow fiber cartridge 16.
  • Tubing 22 and 24 are designated as the supply side of the circulation system 20 supplying medium to the hollow fiber cartridge 16.
  • Medium is circulated back to the supply source 18 by tubing 26.
  • the circulation system 12 is fluidly connected to lumens of hollow fibers 28 of the hollow fiber cartridge 16 in a well known manner.
  • the circulation system 14 supplies medium to the extracapillary space 30 of the hollow fiber cartridge 16, that space being defined as the space between the outer wall surfaces of the hollow fibers and the shell 32 of the hollow fiber cartridge.
  • the circulation system 14 includes a supply source (expansion chamber 34) of medium that supplies medium to the extracapillary space 30 through tubing 36. Medium is returned to the supply source 34 through tubing 38.
  • the tubing 36 and 38 each have monodirectional valves in line so that medium flows in a direction as indicated by arrows 40 and 42.
  • the supply source 34 is kept at a constant pressure by supplying gas to the source 34.
  • the gas pressure is kept constant at approximately 1,1466 bar (100 mmHg above atmospheric).
  • the supply source 18 is also pressurized by gas.
  • the gas pressure is cycled in supply source 18 from 1,0252 to 1,1466 bar (9 to 100 mmHg above atmospheric).
  • the cycling of the gas pressure produces a changing pressure drop across the membrane walls of the hollow fibers and consequently provides a circulation of the medium within the extracapillary space of the hollow fiber cartridge. Circulation of the medium within the extracapillary space of the hollow fiber cartridge provides for minimization of gradients of nutrients and waste products and minimization and/or elimination of microenvironments and anoxic pockets.
  • the system 10 is controlled by a digital computer system (not shown) which controls the pump 20 and the gas pressures in both supply sources 18 and 34 and the cycling of the gas pressure in supply source 18.
  • yield is meant that value obtained by dividing the number of cells initially placed in the hollow fiber cartridge by the number of cells harvested in a sterile condition useful for infusion into a patient.
  • yields Prior to the present invention, using static culturing techniques, yields on the order of approximately 38%-82% were obtained. (Rosenberg et al.) Consequently, a lesser amount of cells were available for infusion to the patient than had been removed from the patient through leukapheresis.
  • subjecting an already weakened patient, for example, a patient suffering from cancer, to extensive leukapheresis is undesirable. Minimizing the leukapheresis by obtaining an equal or a greater amount of cells through culturing of the cells is highly desirable.
  • Adoptive immunotherapy is initially started by obtaining leukoyctes from blood of the patient by subjecting the blood to leukapheresis.
  • the leukapheresis cell suspension is then centrifuged and then separated leukocytes are harvested, washed and inoculated into the extracapillary space of the hollow fiber cartridge.
  • the cartridges (from 1-6) are inoculated with an average of 0.7 x 109 cells/cartridge (0.25 to 2.2 x 109 /cartridge) and the cell culturing system activated to culture the cells.
  • the cells are cultured with recombinant interleukin-2 (rIL-2) obtained from Cetus Corporation of Emeryville, California to produce a lymphokine-activated killer (LAK) cell.
  • rIL-2 recombinant interleukin-2
  • LAK lymphokine-activated killer
  • the LAK cells are removed from the cartridges after culture and activation (4-19 days) and are then administered intravenously through a venous catheter or by direct infusion into an artery via a percutaneous catheter.
  • the effects of such infusion can be observed on a cancerous tumor by techniques well known in the art.
  • the administration of the LAK cells can be continued until the tumor has totally disappeared or until efforts show no further regression of the tumor.
  • rIL-2 can also be administered in conjunction with the infusion of the LAX cells, depending upon the results observed as to the regression of the tumor and the effect of infusion of the LAK cells into the patient.
  • the media used in the circulation loop providing media to the lumina of the hollow fibers was RPMI-1640 (Gibco, New York) containing 2.4mM L-glutamine (12 ml/L of a 200 mM solution), and 50 ug/ml gentamycin (0.5 ml/L of 100 g/L solution) (Sigma, MO).
  • This recirculation media was exchanged every forty-eight hours with fresh recirculation media to replenish the nutrients and rIL2.
  • 500 ml of the medium, having the same composition as the recirculation medium was used to coat the extracapillary space of the hollow fibers in preparation for inoculation of the leukocytes.
  • a unit of blood (approximately 200 ml) was obtained through leukapheresis.
  • the red blood cells were separated from the white blood cells using a ficoll hypaque gradient protocol. The separation was performed in the V50 Haemonetics instrument.
  • the white cells were resuspended in complete RPMI-1640 media (Gibco, New York or Mediatech, VA) containing 8% human serum and 3000 U/ml rIL-2.
  • the concentration of the cells is adjusted to 0.5 - 4.4 x 107 cells per ml and the cells placed in two 60 ml syringes containing approximately 50 ml each of the solution. The cells are injected into the extracapillary space of the bioreactors.
  • the ACUSYST-P feed rate was set to 50 ml per hour.
  • the hollow fiber cartridge was coated 2 to 24 hours prior to inoculation with 500 ml of the coating medium.
  • the ACUSYST-JR is run identically to the ACUSYST-P, however, the volumes of media and cells used are proportional to the number of cartridges used.
  • the cells were cultured in a routine manner by cycling the pressure in the primary circulation system between 1,0132 to 1,1466 bar (0 and 100 mmHg above atmospheric) and keeping the pressure in the expansion chamber constant at approximately 1,1466 bar (100 mmHg above atmospheric). Samples were taken daily from the system to monitor pH, dissolved oxygen, glucose and lactate concentrations. These parameters were being maintained at an optimal set point by adjusting the media feed rate through the IC circuit (circulation system 12).
  • the cells were removed from the extracapillary space of the cartridge using the V50 Haemonetics instrument (Braintree, MA) as a cell concentrator. Cells were flushed from the system with approximately 2 liter of normal saline supplemented with 1% human serum albumin and then concentrated to approximately 350 (250-500) mls. The cells were transferred to a 600 ml IV bag (Travenol, IL). The entire procedure was performed in a sterile fashion.
  • V50 Haemonetics instrument Braintree, MA
  • Cells were flushed from the system with approximately 2 liter of normal saline supplemented with 1% human serum albumin and then concentrated to approximately 350 (250-500) mls. The cells were transferred to a 600 ml IV bag (Travenol, IL). The entire procedure was performed in a sterile fashion.
  • the yield figure is calculated based on the number of cells seeded in the cartridge and the total number of cells removed from the cartridge. In the cell culturing process, a number of cells are lost due to the circulation of the media through the extracapillary space in which the cells are being cultured.
  • the cells obtained from Trials I and II were tested for lytic activity and compared to cells cultured in a static culturing system.
  • the static cells were cultured for 14 days in the same type of medium as the ACUSYST-P cultured cells, and maintained at less than 1 x 106 cells/ml by subculturing.
  • the target cells used in measuring lytic activity were HL-60, K562, Daudi and fresh tumor which are well known in the art. The results of these comparisons are listed in Tables 1 and 2.
  • Tables 1 and 2 indicated that the cells cultured according the the present invention have comparable lytic activity as to cells cultured in a static culturing system. (It should be noted that some values have a standard deviation of greater than 10% and care should be taken in any conclusions made with these values).

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Claims (3)

  1. Procédé de culture de leucocytes comprenant l'étape de cultiver les leucocytes en présence de lymphokine dans une cartouche de fibres creuses pendant au moins quatre jours, pour obtenir une récolte de cellules d'au moins 100%.
  2. Procédé selon la revendication 1, dans lequel la lymphokine est de l'interleukine -2 recombinante.
  3. Procédé selon la revendication 1, dans lequel les leucocytes sont cultivés pendant approximativement 4 à 19 jours.
EP87903509A 1986-04-28 1987-04-27 Procede de culture de leucocytes Expired EP0302894B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT87903509T ATE82588T1 (de) 1986-04-28 1987-04-27 Zuchtverfahren fuer leukocyten.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US85682786A 1986-04-28 1986-04-28
US856827 1986-04-28

Publications (3)

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EP0302894A4 EP0302894A4 (fr) 1989-02-06
EP0302894A1 EP0302894A1 (fr) 1989-02-15
EP0302894B1 true EP0302894B1 (fr) 1992-11-19

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EP87903509A Expired EP0302894B1 (fr) 1986-04-28 1987-04-27 Procede de culture de leucocytes

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US (2) US5541105A (fr)
EP (1) EP0302894B1 (fr)
JP (1) JP2529321B2 (fr)
AT (1) ATE82588T1 (fr)
DE (1) DE3782736T2 (fr)
WO (1) WO1987006610A1 (fr)

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AP1261A (en) 1998-02-24 2004-03-19 Sisters Of Providence In Oregon Composition containing an OX-40 receptor binding agent or a nucleic acid encoding the same and methods for enhancing antigen-specific immune response.
DE19945162A1 (de) * 1999-09-21 2001-04-26 Herbert Maerkl Verfahren zur Kultivierung von Zellen, Membranmodul, Verwendung eines Membranmoduls und Reaktionssystem zur Kultivierung von Zellen
EP2029722B1 (fr) 2006-05-22 2019-10-16 Biovest International, Inc. Procédé et système pour la production de cellules
JP2010519937A (ja) 2007-03-05 2010-06-10 カリディアンビーシーティー、インコーポレーテッド 細胞増殖システムおよび使用方法
ES2665024T3 (es) * 2007-03-05 2018-04-24 Terumo Bct, Inc. Métodos para controlar el movimiento celular en biorreactores de fibra hueca
JP5524824B2 (ja) * 2007-04-06 2014-06-18 テルモ ビーシーティー、インコーポレーテッド 改良されたバイオリアクタ表面
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EP2566951B1 (fr) 2010-05-05 2020-03-04 Terumo BCT, Inc. Procédé de réensemencement de cellules adhérentes cultivées dans un système de bioréacteur à fibres creuses
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WO2012171026A2 (fr) 2011-06-10 2012-12-13 Biovest International, Inc. Procédés pour la production virale à haut rendement
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CN104540933A (zh) 2012-08-20 2015-04-22 泰尔茂比司特公司 在细胞扩增系统的生物反应器中加载和分配细胞的方法
EP2909302A4 (fr) 2012-08-28 2016-07-27 Biovest Int Inc Enfilade de biofabrication et procédé de production à grande échelle de cellules, virus et biomolécules
WO2014036488A1 (fr) 2012-08-31 2014-03-06 Biovest International, Inc. Procédés de production de vaccins idiotypiques autologues haute fidélité
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WO2015073913A1 (fr) 2013-11-16 2015-05-21 Terumo Bct, Inc. Expansion de cellules dans un bioréacteur
WO2015148704A1 (fr) 2014-03-25 2015-10-01 Terumo Bct, Inc. Remplacement passif de milieu
US10077421B2 (en) 2014-04-24 2018-09-18 Terumo Bct, Inc. Measuring flow rate
EP3198006B1 (fr) 2014-09-26 2021-03-24 Terumo BCT, Inc. Alimentation programmée
WO2017004592A1 (fr) 2015-07-02 2017-01-05 Terumo Bct, Inc. Croissance cellulaire à l'aide de stimuli mécaniques
US11965175B2 (en) 2016-05-25 2024-04-23 Terumo Bct, Inc. Cell expansion
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Also Published As

Publication number Publication date
JP2529321B2 (ja) 1996-08-28
DE3782736D1 (de) 1992-12-24
EP0302894A4 (fr) 1989-02-06
US5541105A (en) 1996-07-30
EP0302894A1 (fr) 1989-02-15
WO1987006610A1 (fr) 1987-11-05
DE3782736T2 (de) 1993-06-09
ATE82588T1 (de) 1992-12-15
US5631006A (en) 1997-05-20
JPH01502315A (ja) 1989-08-17

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